Antigen-binding polypeptides directed against cd38

Abstract

Methods of targeting a CD38-expressing cell for treatment of at least one disease, disorder or condition that is associated with CD38. Polypeptides specifically binding to CD38 which are therefore suitable for the diagnosis and for the therapeutic and prophylactic treatment of diseases which are characterized by increased CD38 expression. Conjugates and pharmaceutical compositions comprising the polypeptides are disclosed as well. Use of such polypeptides in methods for the detection of CD38 and/or CD38-expressing cells in a biological sample. A process for the purification and concentration of CD38 and/or CD38-expressing cells in which the antigen-binding polypeptides are used are also described.

1 . A method of targeting a CD38-expressing cell for treatment of at least one disease, disorder or condition that is associated with CD38, said method comprising administering a pharmaceutically active amount of a polypeptide to a subject in need thereof, wherein the polypeptide comprises at least one immunoglobulin single variable domain (ISVD) that specifically binds to an epitope on human CD38 (SEQ ID NO:465) with an EC 50  value of less than 200 nM and does not compete with monoclonal anti-CD38 antibody Daratumumab binding to said CD38, and wherein the at least one ISVD comprises 3 complementarity determining regions (CDRs), wherein
 (i) CDR1 is chosen from the group consisting of SEQ ID NOs: 117-174;   (ii) CDR2 is chosen from the group consisting of SEQ ID NOs: 233-290; and   (iii) CDR3 is chosen from the group consisting of SEQ ID NOs: 349-406.   
     
     
         2 . The method of  claim 1 , wherein said ISVD specifically binds a first epitope of said CD38 and wherein Daratumumab binds to a second epitope of said CD38, wherein said first epitope and said second epitope are different. 
     
     
         3 . The method of  claim 2 , wherein said first epitope and said second epitope do not overlap. 
     
     
         4 . The method of  claim 1 , further comprising a fragment crystallizable portion (Fc portion) linked to said at least one ISVD. 
     
     
         5 . The method of  claim 1 , said method comprising administering to said subject a composition comprising a plurality of said polypeptides and at least one pharmaceutically acceptable carrier, diluent, excipient, and/or adjuvant. 
     
     
         6 . The method of  claim 1 , wherein said CD38-expressing cell is a tumor cell. 
     
     
         7 . The method of  claim 6 , further comprising administering monoclonal anti-CD38 antibody Daratumumab to said subject, wherein said at least one ISVD and said Daratumumab bind to non-overlapping epitopes on CD38 of said tumor cell. 
     
     
         8 . The method of  claim 7 , wherein said at least one ISVD and said Daratumumab demonstrate a synergistic cytotoxic effect against said CD38-expressing tumor cell. 
     
     
         9 . The method of  claim 6 , wherein said polypeptide inhibits growth of said tumor cell. 
     
     
         10 . The method of  claim 1 , wherein said polypeptide comprises at least a second ISVD that specifically binds to an epitope on human CD38, wherein said at least one ISVD binds a first epitope of CD38 and said second ISVD binds a second epitope on CD38, wherein said first epitope is different from said second epitope. 
     
     
         11 . The method of  claim 10 , wherein said first epitope does not overlap with said second epitope. 
     
     
         12 . The method of  claim 10 , wherein said at least two ISVDs are directly linked to each other or linked to each other via a linker. 
     
     
         13 . The method of  claim 12 , in which the linker is selected from the group of linkers with SEQ ID NOs: 482-494. 
     
     
         14 . The method of  claim 1 , wherein
 CDR1 is SEQ ID NO: 117, CDR2 is SEQ ID NO: 233 and CDR3 is SEQ ID NO: 349;   CDR1 is SEQ ID NO: 118, CDR2 is SEQ ID NO: 234 and CDR3 is SEQ ID NO: 350;   CDR1 is SEQ ID NO: 119, CDR2 is SEQ ID NO: 235 and CDR3 is SEQ ID NO: 351;   CDR1 is SEQ ID NO: 120, CDR2 is SEQ ID NO: 236 and CDR3 is SEQ ID NO: 352;   CDR1 is SEQ ID NO: 121, CDR2 is SEQ ID NO: 237 and CDR3 is SEQ ID NO: 353;   CDR1 is SEQ ID NO: 122, CDR2 is SEQ ID NO: 238 and CDR3 is SEQ ID NO: 354;   CDR1 is SEQ ID NO: 123, CDR2 is SEQ ID NO: 239 and CDR3 is SEQ ID NO: 355;   CDR1 is SEQ ID NO: 124, CDR2 is SEQ ID NO: 240 and CDR3 is SEQ ID NO: 356;   CDR1 is SEQ ID NO: 125, CDR2 is SEQ ID NO: 241 and CDR3 is SEQ ID NO: 357;   CDR1 is SEQ ID NO: 126, CDR2 is SEQ ID NO: 242 and CDR3 is SEQ ID NO: 358;   CDR1 is SEQ ID NO: 127, CDR2 is SEQ ID NO: 243 and CDR3 is SEQ ID NO: 359;   CDR1 is SEQ ID NO: 128, CDR2 is SEQ ID NO: 244 and CDR3 is SEQ ID NO: 360;   CDR1 is SEQ ID NO: 129, CDR2 is SEQ ID NO: 245 and CDR3 is SEQ ID NO: 361;   CDR1 is SEQ ID NO: 130, CDR2 is SEQ ID NO: 246 and CDR3 is SEQ ID NO: 362;   CDR1 is SEQ ID NO: 131, CDR2 is SEQ ID NO: 247 and CDR3 is SEQ ID NO: 363;   CDR1 is SEQ ID NO: 132, CDR2 is SEQ ID NO: 248 and CDR3 is SEQ ID NO: 364;   CDR1 is SEQ ID NO: 133, CDR2 is SEQ ID NO: 249 and CDR3 is SEQ ID NO: 365;   CDR1 is SEQ ID NO: 134, CDR2 is SEQ ID NO: 250 and CDR3 is SEQ ID NO: 366;   CDR1 is SEQ ID NO: 135, CDR2 is SEQ ID NO: 251 and CDR3 is SEQ ID NO: 367;   CDR1 is SEQ ID NO: 136, CDR2 is SEQ ID NO: 252 and CDR3 is SEQ ID NO: 368;   CDR1 is SEQ ID NO: 137, CDR2 is SEQ ID NO: 253 and CDR3 is SEQ ID NO: 369;   CDR1 is SEQ ID NO: 138, CDR2 is SEQ ID NO: 254 and CDR3 is SEQ ID NO: 370;   CDR1 is SEQ ID NO: 139, CDR2 is SEQ ID NO: 255 and CDR3 is SEQ ID NO: 371;   CDR1 is SEQ ID NO: 140, CDR2 is SEQ ID NO: 256 and CDR3 is SEQ ID NO: 372;   CDR1 is SEQ ID NO: 141, CDR2 is SEQ ID NO: 257 and CDR3 is SEQ ID NO: 373;   CDR1 is SEQ ID NO: 142, CDR2 is SEQ ID NO: 258 and CDR3 is SEQ ID NO: 374;   CDR1 is SEQ ID NO: 143, CDR2 is SEQ ID NO: 259 and CDR3 is SEQ ID NO: 375;   CDR1 is SEQ ID NO: 144, CDR2 is SEQ ID NO: 260 and CDR3 is SEQ ID NO: 376;   CDR1 is SEQ ID NO: 145, CDR2 is SEQ ID NO: 261 and CDR3 is SEQ ID NO: 377;   CDR1 is SEQ ID NO: 146, CDR2 is SEQ ID NO: 262 and CDR3 is SEQ ID NO: 378;   CDR1 is SEQ ID NO: 147, CDR2 is SEQ ID NO: 263 and CDR3 is SEQ ID NO: 379;   CDR1 is SEQ ID NO: 148, CDR2 is SEQ ID NO: 264 and CDR3 is SEQ ID NO: 380;   CDR1 is SEQ ID NO: 149, CDR2 is SEQ ID NO: 265 and CDR3 is SEQ ID NO: 381;   CDR1 is SEQ ID NO: 150, CDR2 is SEQ ID NO: 266 and CDR3 is SEQ ID NO: 382;   CDR1 is SEQ ID NO: 151, CDR2 is SEQ ID NO: 267 and CDR3 is SEQ ID NO: 383;   CDR1 is SEQ ID NO: 152, CDR2 is SEQ ID NO: 268 and CDR3 is SEQ ID NO: 384;   CDR1 is SEQ ID NO: 153, CDR2 is SEQ ID NO: 269 and CDR3 is SEQ ID NO: 385;   CDR1 is SEQ ID NO: 154, CDR2 is SEQ ID NO: 270 and CDR3 is SEQ ID NO: 386;   CDR1 is SEQ ID NO: 155, CDR2 is SEQ ID NO: 271 and CDR3 is SEQ ID NO: 387;   CDR1 is SEQ ID NO: 156, CDR2 is SEQ ID NO: 272 and CDR3 is SEQ ID NO: 388;   CDR1 is SEQ ID NO: 157, CDR2 is SEQ ID NO: 273 and CDR3 is SEQ ID NO: 389;   CDR1 is SEQ ID NO: 158, CDR2 is SEQ ID NO: 274 and CDR3 is SEQ ID NO: 390;   CDR1 is SEQ ID NO: 159, CDR2 is SEQ ID NO: 275 and CDR3 is SEQ ID NO: 391;   CDR1 is SEQ ID NO: 160, CDR2 is SEQ ID NO: 276 and CDR3 is SEQ ID NO: 392;   CDR1 is SEQ ID NO: 161, CDR2 is SEQ ID NO: 277 and CDR3 is SEQ ID NO: 393;   CDR1 is SEQ ID NO: 162, CDR2 is SEQ ID NO: 278 and CDR3 is SEQ ID NO: 394;   CDR1 is SEQ ID NO: 163, CDR2 is SEQ ID NO: 279 and CDR3 is SEQ ID NO: 395;   CDR1 is SEQ ID NO: 164, CDR2 is SEQ ID NO: 280 and CDR3 is SEQ ID NO: 396;   CDR1 is SEQ ID NO: 165, CDR2 is SEQ ID NO: 281 and CDR3 is SEQ ID NO: 397;   CDR1 is SEQ ID NO: 166, CDR2 is SEQ ID NO: 282 and CDR3 is SEQ ID NO: 398;   CDR1 is SEQ ID NO: 167, CDR2 is SEQ ID NO: 283 and CDR3 is SEQ ID NO: 399;   CDR1 is SEQ ID NO: 168, CDR2 is SEQ ID NO: 284 and CDR3 is SEQ ID NO: 400;   CDR1 is SEQ ID NO: 169, CDR2 is SEQ ID NO: 285 and CDR3 is SEQ ID NO: 401;   CDR1 is SEQ ID NO: 170, CDR2 is SEQ ID NO: 286 and CDR3 is SEQ ID NO: 402;   CDR1 is SEQ ID NO: 171, CDR2 is SEQ ID NO: 287 and CDR3 is SEQ ID NO: 403;   CDR1 is SEQ ID NO: 172, CDR2 is SEQ ID NO: 288 and CDR3 is SEQ ID NO: 404;   CDR1 is SEQ ID NO: 173, CDR2 is SEQ ID NO: 289 and CDR3 is SEQ ID NO: 405; and   CDR1 is SEQ ID NO: 174, CDR2 is SEQ ID NO: 290 and CDR3 is SEQ ID NO: 406.